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How Are Mesenchymal Stem Cells Related to Immunity (Part Two)

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MSCs and inflammation

Since the study found that bone marrow MSCs inhibit the proliferation of T cells, scientists have found that MSCs can widely inhibit the activation and function of a variety of immune cells, including macrophages, granulocytes, natural killer cells, and dendritic cells, T cells and B cells. MSCs not only inhibit T lymphocyte proliferation, but also inhibit the differentiation of initial T cells into Th1 and Th2 cell subsets, and promote the production of regulatory T cells (Treg). Moreover, MSCs can indirectly induce Treg by affecting dendritic cells. In addition, MSCs can promote the conversion of pro-inflammatory type I macrophages to anti-inflammatory type II macrophages, treat sepsis, and down-regulate natural killer cell activation induced by IL-2 or IL-15. This series of powerful immunoregulatory functions has given MSCs the possibility of treating a variety of inflammation-related diseases, and truly realized the efficient clinical application of MSCs.

The immunoregulatory effects of MSCs are closely related to various secreted factors, including TGF-β, NO, IDO, TSG-6, PGE2, IL-1 receptor antagonists, IL-10 and chemokine CCL2 antagonist variants. The diversity of MSCs immune regulation mechanisms may be due to the differences in their species and tissue sources and their microenvironment. In fact, the immune suppressive function of MSCs depends on the stimulation of interferon-γ (IFN-γ) and TNF, IL-1α or IL-1β. Blocking IFN-γR or using IFN-γR61 / 61MSCs cannot effectively exert the immunosuppressive effect of MSC. Stimulated by the above-mentioned inflammatory factors, MSCs express high levels of IDO, iNOS, and ligands of CXCR3 and CCR5, among which chemokines recruit T cells to reach around MSCs, thereby expressing immunosuppressive factors that inhibit T cell function. At this point, there is a close interaction between MSCs and inflammation. A deep understanding of the interaction between MSCs and inflammation is of great significance in guiding the rational clinical application of MSCs and understanding the pathological mechanisms of inflammatory diseases.

In addition to inflammatory factors, other factors are also involved in the "authorization" process of MSCs' immunosuppressive functions. For example, stimulation of Toll-like receptors (TLRs)-TLR3 and TLR4 can activate the immunosuppressive effects of MSCs. MSCs also respond to different inflammatory stimuli and activate different signaling pathways to regulate specific immune responses. These research findings not only help us better understand the mutual regulation of MSCs and the inflammatory microenvironment, but also have important guiding significance for discovering or improving the application potential of MSCs in different diseases, especially immune disorders.

MSCs and immune regulation

The ability of MSCs to regulate immunity depends on the type and concentration of various inflammatory mediators in their microenvironment. Different inflammatory states greatly affect the therapeutic effect of MSCs on diseases, suggesting the plasticity of MSCs immune regulation. Studies have found that MSCs can effectively treat graft-versus-hostdisease (GVHD) under strong inflammation, but if MSCs are infused on the same day as bone marrow transplantation, that is, when the inflammatory response has not yet begun, the treatment effect is not significant. In addition, MSCs have little effect on experimental autoimmune encephalomyelitis in remission. From this point of view, the immunoregulatory ability of MSCs does have a strong plasticity, which is closely related to the inflammatory state.

In the pathological process of inflammatory diseases, high levels of inflammatory factors are often closely related to the acute phase of the disease, while in the chronic or remission phase, the inflammatory factors present relatively low concentrations, which may be the body's self-repair phase. "Checkerboard gradient" concentration was used to detect the immunoregulatory function of MSCs under different concentrations of inflammatory factors (IFN-γ and TNF-α). It was found that the dynamic changes of inflammatory factor levels can affect the immunoregulatory function of MSCs, making them exert immunosuppression or immunostimulatory effects and lay the foundation for the research of the plasticity of immune regulation. The main reason is that low levels of inflammatory factors are not enough to induce MSCs to express high levels of iNOS or IDO. Instead, they will recruit lymphocytes to the surrounding MSCs to secrete a large amount of chemokines and exacerbate the inflammation response.

Therefore, NO and IDO are the “switches” that regulate the immune regulatory function of MSCs. MSCs also exhibited similar immune-enhancing functions in low-dose concanavalin A-activated T-cell co-culture systems. In addition, antigen-sensitized MSCs can be stimulated with low-dose IFN-γ to activate cytotoxic CD8 + T cells as antigen-presenting cells. The above studies suggest that high inflammatory levels stimulate MSCs to exert immunosuppressive functions, while low inflammatory environment levels stimulate MSCs to exert immune promoting effects. Although the mechanism network that regulates MSCs activity in different inflammatory environments has not been clarified, plasticity is the most reasonable explanation for the phenomenon that MSCs exert different immune regulatory functions in different environments.

During the inflammatory process, the cytokines, chemokines and related immune cells of the immune system are dynamically changed, and different immune cells play different functions. Among them, effector T cells and regulatory T cells are important cells that promote inflammation and fight inflammation, respectively. Th1 and Th17 belong to effector T cells with pro-inflammatory effects, and IFN-γ, TNF-α, and IL-17 produced by them lead the pathological process in a variety of autoimmune diseases and infections. In the pathological process of these diseases, MSCs are also recruited to the site of inflammation to participate in regulating the inflammatory response and assist tissue repair or regeneration. Cytokines at the site of inflammation are essential in conferring immunosuppressive function to MSCs, and the synergy between IFN-γ and TNF-α is particularly important. In addition, the presence of IL-17 can enhance the stability of iNOS mRNA in MSCs by regulating the RNA-binding protein AUF1, and significantly promote the immunosuppressive function of MSCs. Therefore, the type and concentration of cytokines in the inflammatory microenvironment determine the immune regulatory capacity of MSCs.

Immunosuppressive factors such as TGF-β, as important factors to maintain the body's immune balance, are also commonly found in the inflammatory microenvironment. TGF-β receptors I and II are expressed on MSCs and regulate their differentiation and regeneration. When TGF-β, IFN-γ, and TNF-α co-stimulate MSCs, the immunosuppressive function of MSCs is significantly reduced, which is related to the down-regulation of iNOS or IDO expression by TGF-β through signal transduction factor Smad3. It is worth mentioning that MSCs can produce a large amount of TGF-β. Therefore, the negative regulation of TGF-β on the immunosuppressive effect of MSCs can be used as a feedback regulation to maintain the inflammatory state of the injury site and regulate tissue regeneration. In addition to TGF-β produced by MSCs, IL-10, which often has similar immunosuppressive effects as TGF-β, can also block the immunosuppressive function of MSCs. From this point of view, cytokines known for their immunosuppressive effects can exert their immune-promoting functions by acting on MSCs.

To be continued in Part Three…

 


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